Dopamine D4 receptor modulates inhibitory transmission in pallido-pallidal terminals and regulates motor behavior.

Two major groups of terminals release GABA within the Globus pallidus; one group is constituted by projections from striatal neurons, while endings of the intranuclear collaterals form the other one. Each neurons' population expresses different subtypes of dopamine D2-like receptors: D2 R subtype is expressed by encephalin-positive MSNs, while pallidal neurons express the D4 R subtype. The D2 R modulates the firing rate of striatal neurons and GABA release at their projection areas, while the D4 R regulates Globus pallidus neurons excitability and GABA release at their projection areas. However, it is unknown if these receptors control GABA release at pallido-pallidal collaterals and regulate motor behavior. Here, we present neurochemical evidence of protein content and binding of D4 R in pallidal synaptosomes, control of [3 H] GABA release in pallidal slices of rat, electrophysiological evidence of the presence of D4 R on pallidal recurrent collaterals in mouse slices, and turning behavior induced by D4 R antagonist microinjected in amphetamine challenged rats. As in projection areas of pallidal neurons, GABAergic transmission in pallido-pallidal recurrent synapses is under modulation of D4 R, while the D2 R subtype, as known, modulates striato-pallidal projections. Also, as in projection areas, D4 R contributes to control the motor activity differently than D2 R. This study could help to understand the organization of intra-pallidal circuitry.

A novel rat robot controlled by electrical stimulation of the nigrostriatal pathway.

OBJECTIVE: Artificial manipulation of animal movement could offer interesting advantages and potential applications using the animal's inherited superior sensation and mobility. Although several behavior control models have been introduced, they generally epitomize virtual reward-based training models. In this model, rats are trained multiple times so they can recall the relationship between cues and rewards. It is well known that activation of one side of the nigrostriatal pathway (NSP) in the rat induces immediate turning toward the contralateral side. However, this NSP stimulation-induced directional movement has not been used for the purpose of animal-robot navigation. In this study, the authors aimed to electrically stimulate the NSP of conscious rats to build a command-prompt rat robot. METHODS: Repetitive NSP stimulation at 1-second intervals was applied via implanted electrodes to induce immediate contraversive turning movements in 7 rats in open field tests in the absence of any sensory cues or rewards. The rats were manipulated to navigate from the start arm to a target zone in either the left or right arm of a T-maze. A leftward trial was followed by a rightward trial, and each rat completed a total of 10 trials. In the control group, 7 rats were tested in the same way without NSP stimulation. The time taken to navigate the maze was compared between experimental and control groups. RESULTS: All rats in the experimental group successfully reached the target area for all 70 trials in a short period of time with a short interstimulus interval (< 0.7 seconds), but only 41% of rats in the control group reached the target area and required a longer period of time to do so. The experimental group made correct directional turning movements at the intersection zone of the T-maze, taking significantly less time than the control group. No significant difference in navigation duration for the forward movements on the start and goal arms was observed between the two groups. However, the experimental group showed quick and accurate movement at the intersection zone, which made the difference in the success rate and elapsed time of tasks. CONCLUSIONS: The results of this study clearly indicate that a rat-robot model based on NSP stimulation can be a practical alternative to previously reported models controlled by virtual sensory cues and rewards.

Measurement of human rotation behavior for psychological and neuropsychological investigations.

The investigation of rotation behavior in human beings enjoys a longstanding and enduring interest in laterality research. While in animal studies the issue of accurately measuring the number of rotations has been solved and is widely applied in practice, it is still challenging to assess the rotation behavior of humans in daily life. We propose a robust method to assess human rotation behavior based on recordings from a miniature inertial measurement unit that can be worn unobtrusively on a belt. We investigate the effect of different combinations of low-cost sensors-including accelerometers, gyroscopes, and magnetometers-on rotation measurement accuracy, propose a simple calibration procedure, and validate the method on data from a predefined path through and around buildings. Results suggest that a rotation estimation based on the fusion of accelerometer, gyroscope, and magnetometer measurements outperforms methods based solely on earth magnetic field measurements, as proposed in previous studies, by a drop in error rate of up to 32 %. We further show that magnetometer signals do not significantly contribute to measurement accuracy in short-term measurements, and could thus be omitted for improved robustness in environments with magnetic field disturbances. Results also suggest that our simple calibration procedure can compete with more complex approaches and reduce the error rate of the proposed algorithm by up to 38 %.

Pilot turning behavior cognitive load analysis in simulated flight.

Background: To identify the cognitive load of different turning tasks in simulated flight, a flight experiment was designed based on real "preliminary screening" training modules for pilots. Methods: Heart Rate Variability (HRV) and flight data were collected during the experiments using a flight simulator and a heart rate sensor bracelet. The turning behaviors in flight were classified into climbing turns, descending turns, and level flight turns. A recognition model for the cognitive load associated with these turning behaviors was developed using machine learning and deep learning algorithms. Results: pnni_20, range_nni, rmssd, sdsd, nni_20, sd1, triangular_index indicators are negatively correlated with different turning load. The LSTM-Attention model excelled in recognizing turning tasks with varying cognitive load, achieving an F1 score of 0.9491. Conclusion: Specific HRV characteristics can be used to analyze cognitive load in different turn-ing tasks, and the LSTM-Attention model can provide references for future studies on the selection characteristics of pilot cognitive load, and offer guidance for pilot training, thus having significant implications for pilot training and flight safety.

Corrigendum: Development under predation risk increases serotonin-signaling, variability of turning behavior and survival in adult fruit flies Drosophila melanogaster.

[This corrects the article DOI: 10.3389/fnbeh.2023.1189301.].

Development under predation risk increases serotonin-signaling, variability of turning behavior and survival in adult fruit flies Drosophila melanogaster.

The development of high-throughput behavioral assays, where numerous individual animals can be analyzed in various experimental conditions, has facilitated the study of animal personality. Previous research showed that isogenic Drosophila melanogaster flies exhibit striking individual non-heritable locomotor handedness. The variability of this trait, i.e., the predictability of left-right turn biases, varies across genotypes and under the influence of neural activity in specific circuits. This suggests that the brain can dynamically regulate the extent of animal personality. It has been recently shown that predators can induce changes in prey phenotypes via lethal or non-lethal effects affecting the serotonergic signaling system. In this study, we tested whether fruit flies grown with predators exhibit higher variability/lower predictability in their turning behavior and higher survival than those grown with no predators in their environment. We confirmed these predictions and found that both effects were blocked when flies were fed an inhibitor (αMW) of serotonin synthesis. The results of this study demonstrate a negative association between the unpredictability of turning behavior of fruit flies and the hunting success of their predators. We also show that the neurotransmitter serotonin controls predator-induced changes in the turning variability of fruit flies, regulating the dynamic control of behavioral predictability.

THE FLAGELLAR PHOTORESPONSE IN VOLVOX SPECIES (VOLVOCACEAE, CHLOROPHYCEAE)1.

Steering their swimming direction toward the light is crucial for the viability of Volvox colonies, the larger members of the volvocine algae. While it is known that this phototactic steering is achieved by a difference in behavior of the flagella on the illuminated and shaded sides, conflicting reports suggest that this asymmetry arises either from a change in beating direction or a change in beating frequency. Here, we report direct observations of the flagellar behavior of various Volvox species with different phyletic origin in response to light intensity changes and thereby resolve this controversy: Volvox barberi W. Shaw from the section Volvox sensu Nozaki (2003) changes the direction of the flagellar beating plane, while species encompassed in the group Eudorina (Volvox carteri F. Stein, Volvox aureus Ehrenb., and Volvox tertius Art. Mey.) decrease the flagellar beating frequency, sometimes down to flagellar arrest.

Knock-Down of GPR88 in the Dorsal Striatum Alters the Response of Medium Spiny Neurons to the Loss of Dopamine Input and L-3-4-Dyhydroxyphenylalanine.

The effects of L-3-4-dyhydroxyphenylalanine (L-DOPA) treatment for replacing the dopamine (DA) loss in Parkinson's disease (PD) progressively wear off and are hindered by the development of dyskinesia, prompting the search for new treatments. The orphan G protein-coupled receptor 88 (Gpr88) represents a potential new target, as it is highly and almost exclusively expressed in the projecting gamma-Aminobutyric Acid-ergic (GABAergic) medium spiny neurons of the striatum, is implicated in motor activity, and is downregulated by 6-hydroxydopamine (6-OHDA) lesions, an effect that is reversed by L-DOPA. Thus, to evaluate Gpr88 as a potential target for the management of PD and L-DOPA-induced dyskinesia (LID), we inactivated Gpr88 by lentiviral-mediated knock-down with a specifically designed microRNA (miR) (KD-Gpr88) in a 6-OHDA rat model of hemiparkinsonism. Then, we investigated the effects of the KD-Gpr88 in the DA-deprived dorsal striatum on circling behavior and LID as well as on specific markers of striatal neuron activity. The KD-Gpr88 reduced the acute amphetamine-induced and increased L-DOPA-induced turning behavior. Moreover, it normalized the upregulated expression of striatal Gad67 and proenkephalin provoked by the 6-OHDA lesion. Finally, despite promoting ΔFosB accumulation, the KD-Gpr88 was associated neither with the upregulation of prodynorphin, which is causally linked to the severity of LID, nor with the aggravation of LID following chronic L-DOPA treatment in 6-OHDA-lesioned rats. These results thus justify further evaluation of Gpr88 as a potentially novel target for the management of PD as an alternative to L-DOPA therapy.

Inverse Control of Turning Behavior by Dopamine D1 Receptor Signaling in Columnar and Ring Neurons of the Central Complex in Drosophila.

Action selection is a prerequisite for decision-making and a fundamental aspect to any goal-directed locomotion; it requires integration of sensory signals and internal states to translate them into action sequences. Here, we introduce a novel behavioral analysis to study neural circuits and mechanisms underlying action selection and decision-making in freely moving Drosophila. We discovered preferred patterns of motor activity and turning behavior. These patterns are impaired in FoxP mutant flies, which present an altered temporal organization of motor actions and turning behavior, reminiscent of indecisiveness. Then, focusing on central complex (CX) circuits known to integrate different sensory modalities and controlling premotor regions, we show that action sequences and turning behavior are regulated by dopamine D1-like receptor (Dop1R1) signaling. Dop1R1 inputs onto CX columnar ellipsoid body-protocerebral bridge gall (E-PG) neuron and ellipsoid body (EB) R2/R4m ring neuron circuits both negatively gate motor activity but inversely control turning behavior. Although flies deficient of D1 receptor signaling present normal turning behavior despite decreased activity, restoring Dop1R1 level in R2/R4m-specific circuitry affects the temporal organization of motor actions and turning. We finally show EB R2/R4m neurons are in contact with E-PG neurons that are thought to encode body orientation and heading direction of the fly. These findings suggest that Dop1R1 signaling in E-PG and EB R2/4 m circuits are compared against each other, thereby modulating patterns of activity and turning behavior for goal-directed locomotion.

A novel turning behavior control method for rat-robot through the stimulation of ventral posteromedial thalamic nucleus.

The concept of a rat-robot was initially introduced in 2002, bringing to the field, a novel area of research using modern research into neuroscience and robotics. This paper brings to the table, a study into the method best used for navigation systems in a rat-robot. Current research is epitomized by the use of reward-based spatial navigation, combining the concept of an induced reward sensation as well as a 'virtual touch' sensation to control the movement of the rat-robot. However, such methods are plagued by limitations affecting the success rate as well as preparation procedures which may have varying effects on different rats, even under similar conditions. Hence, this paper studies the stimulation of two different portions of the brain to induce a turning motion within the rat, namely the Ventral Posteromedial (VPM) thalamic nucleus as well as the Barrel-Field (BF) cortex and demonstrates the preferential usage of VPM as the choice use of navigational control in a rat-robot.

cdc-25.4, a Caenorhabditis elegans Ortholog of cdc25, Is Required for Male Mating Behavior.

Cell division cycle 25 (cdc25) is an evolutionarily conserved phosphatase that promotes cell cycle progression. Among the four cdc25 orthologs in Caenorhabditis elegans, we found that cdc-25.4 mutant males failed to produce outcrossed progeny. This was not caused by defects in sperm development, but by defects in male mating behavior. The cdc-25.4 mutant males showed various defects during male mating, including contact response, backing, turning, and vulva location. Aberrant turning behavior was the most prominent defect in the cdc-25.4 mutant males. We also found that cdc-25.4 is expressed in many neuronal cells throughout development. The turning defect in cdc-25.4 mutant males was recovered by cdc-25.4 transgenic expression in neuronal cells, suggesting that cdc-25.4 functions in neurons for male mating. However, the neuronal morphology of cdc-25.4 mutant males appeared to be normal, as examined with several neuronal markers. Also, RNAi depletion of wee-1.3, a C. elegans ortholog of Wee1/Myt1 kinase, failed to suppress the mating defects of cdc-25.4 mutant males. These findings suggest that, for successful male mating, cdc-25.4 does not target cell cycles that are required for neuronal differentiation and development. Rather, cdc-25.4 likely regulates noncanonical substrates in neuronal cells.

Early exposure to dynamic environments alters patterns of motor exploration throughout the lifespan.

We assessed early rearing conditions on aging-related changes in mouse behavior. Two isolated-housing groups, running wheel (IHRW) and empty cage (IHEC), were compared against two enriched environments, static (EEST) and dynamic (EEDY), both of which included toys and other mice. For EEDY, the location of toys and sources of food and water changed daily, but remained constant for EEST. All mice, randomly assigned to one of the four groups at ∼4 weeks of age, remained in their respective environments for 25 weeks followed by single housing in empty cages. Beginning at ∼40 weeks of age, all mice were tested at monthly intervals in a plus-shaped maze in which we measured the number of arm entries and the probability of entering a perpendicular arm. Despite making significantly more arm entries than any other group, IHEC mice also were less likely to turn into the left or right arm, a sign of motor inflexibility. Both EEDY and EEST mice showed enhanced turning relative to IHRW and IHEC groups, but only EEDY mice maintained their turning performance for up to ∼100 weeks of age. EEDY and EEST mice also were unique in showing an increase in expression of the major glutamate transporter (GLT1) in striatum, but a decrease in motor cortex, suggesting a need for further assessment of environmental manipulations on long-term changes in forebrain glutamate transmission. Our behavioral results indicate that early exposure to continually changing environments, rather than socialization or exercise alone, results in life-long changes in patterns of motor exploration.

In vivo dopamine agonist properties of rotigotine: Role of D1 and D2 receptors.

Rotigotine acts in vitro as a full agonist of dopamine D1 receptors at concentrations almost superimposable to those at which it acts on D2 receptors. However in vivo evidence of the differences between the agonist activity of rotigotine at D1 receptors from that on the D2 receptors has not been provided yet. In order to test the ability of rotigotine to stimulate dopamine D1 and D2 receptors in vivo, we studied the effect of SCH39166 and eticlopride, selective dopamine D1 and D2/D3 receptor antagonists respectively, on rotigotine-induced contralateral turning behavior in 6-hydroxydopamine lesioned rats. Furthermore, the expression of the immediate-early gene c-fos in the caudate-putamen, was evaluated. As a comparison, we tested the D2/D3 agonist pramipexole. In primed rats, rotigotine (0.035, 0.1 and 0.35mg/kg) induced dose-dependent contralateral turning. Turning induced by 0.1mg/kg of rotigotine was reduced by pretreatment with the D1 antagonist SCH39166 and the D2 antagonist eticlopride. In drug-naive rats, rotigotine was less effective in eliciting turning but SCH39166 still reduced turning induced by rotigotine (0.35mg/kg). Pramipexole induced contralateral turning only in primed rats. SCH39166 potentiated and eticlopride abolished pramipexole-induced turning. Rotigotine induced Fos expression in the caudate-putamen and SCH39166 completely blocked it. Pramipexole failed to induce Fos. These results indicate that rotigotine acts in vivo as an agonist of D1 and D2 receptors while pramipexole is devoid of D1 activity in vivo. Given their differing DA receptor profiles, rotigotine and pramipexole might differ in their spectrum of application to the therapy of Parkinson's disease.

GABAA-receptor activation in the subthalamic nucleus compensates behavioral asymmetries in the hemiparkinsonian rat.

The subthalamic nucleus (STN) has a pivotal role in the pathophysiology of Parkinson's disease (PD). Modulation of STN activity (by lesions, pharmacological or electrical stimulation) has been shown to improve motor parameters in PD patients and in animal models of PD. In an attempt to characterize the neurochemical bases for such antiparkinsonian action, we address specific neurotransmitter systems via local pharmacological manipulation of the STN in hemiparkinsonian rats. Here, we have focused on the GABAergic and glutamatergic receptors in the STN. In animals with unilateral 6-hydroxydopamine lesions of the nigro-striatal tract, we administered either the selective GABAA-agonist muscimol (0.5 µg and 1.0 µg), the non-competitive N-methyl-d-aspartate (NMDA)-antagonist MK-801 (dizocilpine; 2.5 µg), or vehicle (0.25 µl) into the STN. The effects of GABAergic and glutamatergic modulation of the STN on motor parameters were assessed by gauging rotational behavior and locomotion. Application of muscimol ipsilateral to the side of dopamine-depletion influenced turning behavior in a dose-dependent fashion, with the low dose re-adjusting turning behavior to a non-biased distribution, and the high dose evoking contraversive turning. The administration of MK-801 did not have such effects. These findings give evidence for the involvement of GABAergic activation in the STN in the compensation of motor asymmetries in the hemiparkinsonian rat, whereas N-methyl-d-aspartate (NMDA)-antagonism was ineffective in this model of PD.

Effects of Hypericum perforatum on turning behavior in an animal model of Parkinson's disease

Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by the slow and progressive death of dopaminergic neurons in the (substantia nigra pars compact). Hypericum perforatum (H. perforatum) is a plant widely used as an antidepressant, that also presents antioxidant and anti-inflammatory properties. We evaluated the effects of H. perforatum on the turning behavior of rats submitted to a unilateral administration of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle as an animal model of PD. The animals were treated with H. perforatum (100, 200, or 400 mg/kg, v.o.) for 35 consecutive days (from the 28th day before surgery to the 7th day after). The turning behavior was evaluated at 7, 14 and 21 days after the surgery, and the turnings were counted as contralateral or ipsilateral to the lesion side. All tested doses significantly reduced the number of contralateral turns in all days of evaluation, suggesting a neuroprotective effect. However, they were not able to prevent the 6-OHDA-induced decrease of tyrosine hydroxylase expression in the lesioned striatum. We propose that H. perforatum may counteract the overexpression of dopamine receptors on the lesioned striatum as a possible mechanism for this effect. The present findings provide new evidence that H. perforatum may represent a promising therapeutic tool for PD.

A Doença de Parkinson é uma doença neurodegenerativa relacionada à idade, caracterizada pela morte lenta e progressiva de neurônios dopaminérgicos da substância negra pars compacta. O Hypericum perforatum (H. perforatum) é um fitoterápico utilizado como antidepressivo, apresentando propriedades antioxidantes, anti-inflamatórias e nootrópicas. Neste trabalho, avaliaram-se os efeitos do tratamento com H. perforatum no comportamento rotatório de ratos no modelo da doença de Parkinson induzido pela administração unilateral de 6-OHDA no feixe prosencefálico medial. Ratos Wistar machos foram tratados com H. perforatum (100, 200 ou 400 mg/kg, v.o.) por 35 dias (do 28º dia antes até o 7º dia após a lesão). As rotações ipsilaterais e contralaterais à lesão foram registradas no 7º, 14º e 21º dias após a cirurgia. As três doses de H. perforatum utilizadas reduziram o número de rotações contralaterais, indicando um possível efeito neuroprotetor da planta. Porém, o H. perforatum não impediu a redução na expressão da enzima tirosina hidroxilase no estriado lesionado, quantificada por Western blot. Propomos que o H. perforatum possa bloquear o aumento da expressão dos receptores dopaminérgicos no estriado lesionado com 6-OHDA. Entretanto, estudos adicionais são necessários para identificar o mecanismo exato pelo qual o H. perforatum reduziu o número de rotações contralaterais. Os resultados do presente estudo sugerem o H. perforatum como um potencial agente terapêutico para a doença de Parkinson.